tbuckley/cabot-search huggingface dataset:
IL-3 receptor signalling suppresses chronic intestinal inflammation by controlling mechanobiology and tissue egress of regulatory T cells
Authors: Karen Anne-Marie Ullrich, Julia Derdau, Carsten Baltes, Alice Battistella, Gonzalo Rosso, Stefan Uderhardt, Lisa Lou Schulze, Li-Juan Liu, Mark Dedden, Marta Spocinska, Lucina Kainka, Markéta Kubánková, Tanja Martina Müller, Nina-Maria Schmidt, Emily Becker, Oumaima Ben Brahim, Imke Atreya, Susetta Finotto, Iryna Prots, Stefan Wirtz, Benno Weigmann, Rocío López-Posadas, Raja Atreya, Arif Bülent Ekici, Franziska Lautenschläger, Jochen Guck, Markus F Neurath, Sebastian Zundler
Journal: Gut (2023)

IL-3 has been reported to be involved in various inflammatory disorders, but its role in inflammatory bowel disease (IBD) has not been addressed so far. Here, we determined IL-3 expression in samples from patients with IBD and studied the impact of Il3 or Il3r deficiency on T cell-dependent experimental colitis. We explored the mechanical, cytoskeletal and migratory properties of Il3r −/− and Il3r +/+ T cells using real-time deformability cytometry, atomic force microscopy, scanning electron microscopy, fluorescence recovery after photobleaching and in vitro and in vivo cell trafficking assays. We observed that, in patients with IBD, the levels of IL-3 in the inflamed mucosa were increased. In vivo , experimental chronic colitis on T cell transfer was exacerbated in the absence of Il-3 or Il-3r signalling. This was attributable to Il-3r signalling-induced changes in kinase phosphorylation and actin cytoskeleton structure, resulting in increased mechanical deformability and enhanced egress of Tregs from the inflamed colon mucosa. Similarly, IL-3 controlled mechanobiology in human Tregs and was associated with increased mucosal Treg abundance in patients with IBD. Collectively, our data reveal that IL-3 signaling exerts an important regulatory role at the interface of biophysical and migratory T cell features in intestinal inflammation and suggest that this might be an interesting target for future intervention.
VPS35 and α-Synuclein fail to interact to modulate neurodegeneration in rodent models of Parkinson’s disease
Authors: Xi Chen, Elpida Tsika, Nathan Levine, Darren J. Moore
Journal: Molecular Neurodegeneration (2023)

Mutations in the vacuolar protein sorting 35 ortholog (VPS35) gene cause late-onset, autosomal dominant Parkinson's disease (PD), with a single missense mutation (Asp620Asn, D620N) known to segregate with disease in families with PD. The VPS35 gene encodes a core component of the retromer complex, involved in the endosomal sorting and recycling of transmembrane cargo proteins. VPS35-linked PD is clinically indistinguishable from sporadic PD, although it is not yet known whether VPS35-PD brains exhibit α-synuclein-positive brainstem Lewy pathology that is characteristic of sporadic cases. Prior studies have suggested a functional interaction between VPS35 and the PD-linked gene product α-synuclein in lower organisms, where VPS35 deletion enhances α-synuclein-induced toxicity. In mice, VPS35 overexpression is reported to rescue hippocampal neuronal loss in human α-synuclein transgenic mice, potentially suggesting a retromer deficiency in these mice.Here, we employ multiple well-established genetic rodent models to explore a functional or pathological interaction between VPS35 and α-synuclein in vivo.We find that endogenous α-synuclein is dispensable for nigrostriatal pathway dopaminergic neurodegeneration induced by the viral-mediated delivery of human D620N VPS35 in mice, suggesting that α-synuclein does not operate downstream of VPS35. We next evaluated retromer levels in affected brain regions from human A53T-α-synuclein transgenic mice, but find normal levels of the core subunits VPS35, VPS26 or VPS29. We further find that heterozygous VPS35 deletion fails to alter the lethal neurodegenerative phenotype of these A53T-α-synuclein transgenic mice, suggesting the absence of retromer deficiency in this PD model. Finally, we explored the neuroprotective capacity of increasing VPS35 expression in a viral-based human wild-type α-synuclein rat model of PD. However, we find that the overexpression of wild-type VPS35 is not sufficient for protection against α-synuclein-induced nigral dopaminergic neurodegeneration, α-synuclein pathology and reactive gliosis.Collectively, our data suggest a limited interaction of VPS35 and α-synuclein in neurodegenerative models of PD, and do not provide support for their interaction within a common pathophysiological pathway.
CRIP1 fosters MDSC trafficking and resets tumour microenvironment via facilitating NF-κB/p65 nuclear translocation in pancreatic ductal adenocarcinoma
Authors: Xiaomeng Liu, Rong Tang, Jin Xu, Zhen Tan, Chen Liang, Qingcai Meng, Yubin Lei, Jie Hua, Yiyin Zhang, Jiang Liu, Bo Zhang, Wei Wang, Xianjun Yu, Si Shi
Journal: Gut (2023)

Objective Pancreatic ductal adenocarcinoma (PDAC) is among the most immunosuppressive tumour types. The tumour immune microenvironment (TIME) is largely driven by interactions between immune cells and heterogeneous tumour cells. Here, we aimed to investigate the mechanism of tumour cells in TIME formation and provide potential combination treatment strategies for PDAC patients based on genotypic heterogeneity. Design Highly multiplexed imaging mass cytometry, RNA sequencing, mass cytometry by time of flight and multiplex immunofluorescence staining were performed to identify the pro-oncogenic proteins associated with low immune activation in PDAC. An in vitro coculture system, an orthotopic PDAC allograft tumour model, flow cytometry and immunohistochemistry were used to explore the biological functions of cysteine-rich intestinal protein 1 (CRIP1) in tumour progression and TIME formation. RNA sequencing, mass spectrometry and chromatin immunoprecipitation were subsequently conducted to investigate the underlying mechanisms of CRIP1. Results Our results showed that CRIP1 was frequently upregulated in PDAC tissues with low immune activation. Elevated CRIP1 expression induced high levels of myeloid-derived suppressor cell (MDSC) infiltration and fostered an immunosuppressive tumour microenvironment. Mechanistically, we primarily showed that CRIP1 bound to nuclear factor kappa-B (NF-κB)/p65 and facilitated its nuclear translocation in an importin-dependent manner, leading to the transcriptional activation of CXCL1/5. PDAC-derived CXCL1/5 facilitated the chemotactic migration of MDSCs to drive immunosuppression. SX-682, an inhibitor of CXCR1/2, blocked tumour MDSC recruitment and enhanced T-cell activation. The combination of anti-PD-L1 therapy with SX-682 elicited increased CD8+T cell infiltration and potent antitumor activity in tumour-bearing mice with high CRIP1 expression. Conclusions The CRIP1/NF-κB/CXCL axis is critical for triggering immune evasion and TIME formation in PDAC. Blockade of this signalling pathway prevents MDSC trafficking and thereby sensitises PDAC to immunotherapy.
Single-Cell RNA Analysis Reveals Cell-Intrinsic Functions of CAR T Cells Correlating with Response in a Phase II Study of Lymphoma Patients
Authors: Tina Sarén, Mohanraj Ramachandran, Gustav Gammelgård, Tanja Lövgren, Claudio Mirabello, Åsa K. Björklund, Kristina Wikström, Jamileh Hashemi, Eva Freyhult, Håkan Ahlström, Rose-Marie Amini, Hans Hagberg, Angelica Loskog, Gunilla Enblad, Magnus Essand
Journal: Clinical Cancer Research (2023)

Although CD19 chimeric antigen receptor T cells (CAR-T) therapy has shown remarkable success in B-cell malignancies, a substantial fraction of patients do not obtain a long-term clinical response. This could be influenced by the quality of the individual CAR-T infusion product. To shed some light on this, clinical outcome was correlated to characteristics of CAR-T infusion products.In this phase II study, patients with B-cell lymphoma (n = 23) or leukemia (n = 1) received one or two infusions of third-generation CD19-directed CAR-Ts (2 × 108/m2). The clinical trial was registered at clinicaltrials.gov: NCT03068416. We investigated the transcriptional profile of individual CD19 CAR-T infusion products using targeted single-cell RNA sequencing and multicolor flow cytometry.Two CAR-T infusions were not better than one in the settings used in this study. As for the CAR-T infusion products, we found that effector-like CD8+CAR-Ts with a high polyfunctionality, high cytotoxic and cytokine production profile, and low dysfunctional signature were associated with clinical response. An extended ex vivo expansion time during CAR-T manufacturing negatively influenced the proportion of effector CD8+CAR-Ts in the infusion product.We identified cell-intrinsic characteristics of effector CD8+CAR-Ts correlating with response that could be used as an indicator for clinical outcome. The results in the study also serve as a guide to CAR-T manufacturing practices.
Therapeutic Vaccination against Human Papillomavirus Type 16 for the Treatment of High-Grade Anal Intraepithelial Neoplasia in HIV+ Men
Authors: Karien C.M. Gosens, Sjoerd H. van der Burg, Marij J.P. Welters, Sanne Boekestijn, Nikki M. Loof, Wim G.V. Quint, Carel J.M. van Noesel, Allard C. van der Wal, Olivier Richel, Wilhelmus J.T.A. Krebber, Cornelis J.M. Melief, Henry J.C. de Vries, Jan M. Prins
Journal: Clinical Cancer Research (2023)

Anal cancer is increasing in HIV+ men who have sex with men (MSM). Treatment options for its precursor, high-grade anal intraepithelial neoplasia (HGAIN), are suboptimal. In this phase I to II dose-finding study, we assessed the safety and efficacy of the human papillomavirus type 16 (HPV16) synthetic long peptide vaccine (SLP-HPV-01) in HIV+ MSM with HPV16-positive HGAIN.Four dosage schedules (1-5-10; 5-10-20; 10-20-40; and 40-40-40-40 μg) of SLP-HPV-01 were administered intradermally with a 3-week interval in 10 patients per dose level (DL). In each dose group, 5 patients also received 1 μg/kg pegylated IFNα-2b subcutaneously. Primary endpoints were safety and regression of HGAIN at 3, 6, and 12 months.Eighty-one of 134 screened patients (60%) had HPV16-negative HGAIN lesions, leaving 53 eligible patients. Thirteen patients were excluded, leaving 40 men. The vaccine was well tolerated. One patient developed a generalized rash. The highest dosage level induced the strongest immune responses. There was no indication for stronger reactivity in the IFNα groups. Up to 18 months of follow-up, 8/38 intention-to-treat patients had a complete clinical and histologic response and one had a partial response (in total 9/38, 23.7%). At the highest dosage level, the clinical response was 4/10 (40%). Stronger immune responses were detected among clinical responders.The highest DL is safe, immunogenic, and associated with clinical responses to HPV16-induced lesions. However, as the majority of HGAIN is caused by the other HPV types, further studies should aim at pan-HPV vaccination to prevent or treat HGAIN.
Neoantigen Targetability in Progressive Advanced Melanoma
Authors: Jitske van den Bulk, Els M.E. Verdegaal, Manon van der Ploeg, Marten Visser, Joana B. Nunes, Arnoud H. de Ru, Rayman T.N. Tjokrodirijo, Marieke E. Ijsselsteijn, Natasja I. Janssen, Ruud van der Breggen, Linda de Bruin, Pita de Kok, George M.C. Janssen, Dina Ruano, Ellen H.W. Kapiteijn, Peter A. van Veelen, Noel F.C.C. de Miranda, Sjoerd H. van der Burg
Journal: Clinical Cancer Research (2023)

The availability of (neo)antigens and the infiltration of tumors by (neo)antigen-specific T cells are crucial factors in cancer immunotherapy. In this study, we aimed to investigate the targetability of (neo)antigens in advanced progessive melanoma and explore the potential for continued T-cell-based immunotherapy.We examined a cohort of eight patients with melanoma who had sequential metastases resected at early and later time points. Antigen-presenting capacity was assessed using IHC and flow cytometry. T-cell infiltration was quantified through multiplex immunofluorescence. Whole-exome and RNA sequencing were conducted to identify neoantigens and assess the expression of neoantigens and tumor-associated antigens. Mass spectrometry was used to evaluate antigen presentation. Tumor recognition by autologous T cells was assessed by coculture assays with cell lines derived from the metastatic lesions.We observed similar T-cell infiltration in paired early and later metastatic (LM) lesions. Although elements of the antigen-presenting machinery were affected in some LM lesions, both the early and later metastasis-derived cell lines were recognized by autologous T cells. At the genomic level, the (neo)antigen landscape was dynamic, but the (neo)antigen load was stable between paired lesions.Our findings indicate that subsequently isolated tumors from patients with late-stage melanoma retain sufficient antigen-presenting capacity, T-cell infiltration, and a stable (neo)antigen load, allowing recognition of tumor cells by T cells. This indicates a continuous availability of T-cell targets in metastases occurring at different time points and supports further exploration of (neo)antigen-specific T-cell-based therapeutic approaches for advanced melanoma.
Oncolytic viruses and antibodies: are they more successful when delivered separately or when engineered as a single agent?
Authors: Peter Kok-Ting Wan, Ricardo A Fernandes, Leonard W Seymour
Journal: Journal for ImmunoTherapy of Cancer (2023)

Oncolytic viruses (OVs) provide the promise of tumor-selective cytotoxicity coupled with amplification of the therapeutic agent (the virus) in situ within the tumor improving its therapeutic index. Despite this promise, however, single agent-treatments have not been as successful as combination therapies, particularly combining with checkpoint inhibitor antibodies. The antibodies may be delivered by two approaches, either encoded within the OV genome to restrict antibody production to sites of active virus infection or alternatively given alongside OVs as separate treatments. Both approaches have shown promising therapeutic outcomes, and this leads to an interesting question of whether one approach is potentially better than the other. In this review, we provide a brief summary of the combination OV-antibody therapies that target tumor cells, tumor microenvironment and immune cells to help define key parameters influencing which approach is superior, thereby improving insight into the rational design of OV treatment strategies.
Cell-Free DNA Detects <i>Pseudomonas aeruginosa</i> Lung Infection in Modulator-treated People with Cystic Fibrosis
Authors: Dustin R. Long, Elizabeth A. Holmes, Christopher H. Goss, Pradeep K. Singh, Adam Waalkes, Stephen J. Salipante
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Cell-Free DNA Detects Pseudomonas aeruginosa Lung Infection in Modulator-treated People with Cystic Fibrosis." American Journal of Respiratory and Critical Care Medicine, 208(9), pp. 944–947
The diapause-like colorectal cancer cells induced by SMC4 attenuation are characterized by low proliferation and chemotherapy insensitivity
Authors: Xuedan Sun, Lifang He, Hong Liu, Rick Francis Thorne, Taofei Zeng, Liu Liu, Bo Zhang, Miao He, Yabin Huang, Mingyue Li, Enyi Gao, Mengyao Ma, Cheng Cheng, Fanzheng Meng, Chuandong Lang, Hairui Li, Wanxiang Xiong, Shixiang Pan, Delong Ren, Bingyi Dang, Yi Yang, Mian Wu, Lianxin Liu
Journal: Cell Metabolism (2023)
SARS-CoV-2 Omicron BA.1 breakthrough infection drives late remodeling of the memory B cell repertoire in vaccinated individuals
Authors: Aurélien Sokal, Giovanna Barba-Spaeth, Lise Hunault, Ignacio Fernández, Matteo Broketa, Annalisa Meola, Slim Fourati, Imane Azzaoui, Alexis Vandenberghe, Pauline Lagouge-Roussey, Manon Broutin, Anais Roeser, Magali Bouvier-Alias, Etienne Crickx, Laetitia Languille, Morgane Fournier, Marc Michel, Bertrand Godeau, Sébastien Gallien, Giovanna Melica, Yann Nguyen, Florence Canoui-Poitrine, France Pirenne, Jérôme Megret, Jean-Michel Pawlotsky, Simon Fillatreau, Claude-Agnès Reynaud, Jean-Claude Weill, Félix A. Rey, Pierre Bruhns, Matthieu Mahévas, Pascal Chappert
Journal: Immunity (2023)
TMEM63 proteins function as monomeric high-threshold mechanosensitive ion channels
Authors: Wang Zheng, Shaun Rawson, Zhangfei Shen, Elakkiya Tamilselvan, Harper E. Smith, Julia Halford, Chen Shen, Swetha E. Murthy, Maximilian H. Ulbrich, Marcos Sotomayor, Tian-Min Fu, Jeffrey R. Holt
Journal: Neuron (2023)
Neuronal γ-secretase regulates lipid metabolism, linking cholesterol to synaptic dysfunction in Alzheimer’s disease
Authors: Sofia Essayan-Perez, Thomas C. Südhof
Journal: Neuron (2023)

Presenilin mutations that alter γ-secretase activity cause familial Alzheimer's disease (AD), whereas ApoE4, an apolipoprotein for cholesterol transport, predisposes to sporadic AD. Both sporadic and familial AD feature synaptic dysfunction. Whether γ-secretase is involved in cholesterol metabolism and whether such involvement impacts synaptic function remains unknown. Here, we show that in human neurons, chronic pharmacological or genetic suppression of γ-secretase increases synapse numbers but decreases synaptic transmission by lowering the presynaptic release probability without altering dendritic or axonal arborizations. In search of a mechanism underlying these synaptic impairments, we discovered that chronic γ-secretase suppression robustly decreases cholesterol levels in neurons but not in glia, which in turn stimulates neuron-specific cholesterol-synthesis gene expression. Suppression of cholesterol levels by HMG-CoA reductase inhibitors (statins) impaired synaptic function similar to γ-secretase inhibition. Thus, γ-secretase enables synaptic function by maintaining cholesterol levels, whereas the chronic suppression of γ-secretase impairs synapses by lowering cholesterol levels.
Three-month tapering and discontinuation of long- term, low-dose glucocorticoids in senior patients with rheumatoid arthritis is feasible and safe: placebo-controlled double blind tapering after the GLORIA trial
Authors: Abdullah Ali Hadi Almayali, Maarten Boers, Linda Hartman, Daniela Opris, Reinhard Bos, Marc R Kok, Jose AP Da Silva, Ed Griep, Ruth Klaasen, Cornelia F Allaart, Paul Baudoin, Hennie G Raterman, Zoltan Szekanecz, Frank Buttgereit, Pavol Masaryk, Willem Lems, Yvo Smulders, Maurizio Cutolo, Marieke M ter Wee
Journal: Annals of the Rheumatic Diseases (2023)

The randomised placebo-controlled GLORIA (Glucocorticoid LOw-dose in RheumatoId Arthritis) trial evaluated the benefits and harms of prednisolone 5 mg/day added to standard care for 2 years in patients aged 65+ years with rheumatoid arthritis (RA). Here, we studied disease activity, flares and possible adrenal insufficiency after blinded withdrawal of study medication.Per protocol, patients successfully completing the 2-year trial period linearly tapered and stopped blinded study medication in 3 months. We compared changes in disease activity after taper between treatment groups (one-sided testing). Secondary outcomes (two-sided tests) comprised disease flares (DAS28 (Disease Activity Score 28 joints) increase >0.6, open-label glucocorticoids or disease-modifying antirheumatic drug (DMARD) increase/switch after week 4 of tapering) and symptoms/signs of adrenal insufficiency. In a subset of patients from 3 Dutch centres, cortisol and ACTH were measured in spot serum samples after tapering.191 patients were eligible; 36 met treatment-related flare criteria and were only included in the flare analysis. Mean (SD) DAS28 change at follow-up: 0.2 (1.0) in the prednisolone group (n=76) vs 0.0 (1.2) in placebo (n=79). Adjusted for baseline, the between-group difference in DAS28 increase was 0.16 (95% confidence limit -0.06, p=0.12). Flares occurred in 45% of prednisolone patients compared with 33% in placebo, relative risk (RR) 1.37 (95% CI 0.95 to 1.98; p=0.12). We found no evidence for adrenal insufficiency.Tapering prednisolone moderately increases disease activity to the levels of the placebo group (mean still at low disease activity levels) and numerically increases the risk of flare without evidence for adrenal insufficiency. This suggests that withdrawal of low-dose prednisolone is feasible and safe after 2 years of administration.
Towards in silico CLIP-seq: predicting protein-RNA interaction via sequence-to-signal learning
Authors: Marc Horlacher, Nils Wagner, Lambert Moyon, Klara Kuret, Nicolas Goedert, Marco Salvatore, Jernej Ule, Julien Gagneur, Ole Winther, Annalisa Marsico
Journal: Genome biology (2023)

Abstract We present RBPNet, a novel deep learning method, which predicts CLIP-seq crosslink count distribution from RNA sequence at single-nucleotide resolution. By training on up to a million regions, RBPNet achieves high generalization on eCLIP, iCLIP and miCLIP assays, outperforming state-of-the-art classifiers. RBPNet performs bias correction by modeling the raw signal as a mixture of the protein-specific and background signal. Through model interrogation via Integrated Gradients, RBPNet identifies predictive sub-sequences that correspond to known and novel binding motifs and enables variant-impact scoring via in silico mutagenesis. Together, RBPNet improves imputation of protein-RNA interactions, as well as mechanistic interpretation of predictions.
EVs-mediated delivery of CB2 receptor agonist for Alzheimer's disease therapy
Authors: Yanjing Zhu, Ruiqi Huang, Deheng Wang, Liqun Yu, Yuchen Liu, Runzhi Huang, Shuai Yin, Xiaolie He, Bairu Chen, Zhibo Liu, Liming Cheng, Rongrong Zhu
Journal: Asian Journal of Pharmaceutical Sciences (2023)

Alzheimer's disease (AD) is a typical neurodegenerative disease that leads to irreversible neuronal degeneration, and effective treatment remains elusive due to the unclear mechanism. We utilized biocompatible mesenchymal stem cell-derived extracellular vesicles as carriers loaded with the CB2 target medicine AM1241 (EVs-AM1241) to protect against neurodegenerative progression and neuronal function in AD model mice. According to the results, EVs-AM1241 were successfully constructed and exhibited better bioavailability and therapeutic effects than bare AM1241. The Morris water maze (MWM) and fear conditioning tests revealed that the learning and memory of EVs-AM1241-treated model mice were significantly improved. In vivo electrophysiological recording of CA1 neurons indicated enhanced response to an auditory conditioned stimulus following fear learning. Immunostaining and Western blot analysis showed that amyloid plaque deposition and amyloid β (Aβ)-induced neuronal apoptosis were significantly suppressed by EVs-AM1241. Moreover, EVs-AM1241 increased the number of neurons and restored the neuronal cytoskeleton, indicating that they enhanced neuronal regeneration. RNA sequencing revealed that EVs-AM1241 facilitated Aβ phagocytosis, promoted neurogenesis and ultimately improved learning and memory through the calcium-Erk signaling pathway. Our study showed that EVs-AM1241 efficiently reversed neurodegenerative pathology and enhanced neurogenesis in model mice, indicating that they are very promising particles for treating AD.